Not applicable.
Not applicable.
This invention relates to processes for deoxyfluorinating the pentose sugar of a nucleoside to form the corresponding 2-xcex2-fluoro-arabinose compounds.
The development of safe, efficient, and simple methods for selective incorporation of fluorine into organic compounds has become a very important area of technology. It is of particular importance with respect to the deoxyfluorination of the pentose sugar component of a nucleoside to form 2-xcex2-fluoro-arabinose compounds, which have been shown to exhibit potent anti-tumor and anti-viral activity. See, e.g., Wright et al., 13(2) J. Med. Chem. 269-72 (1970); Fanucchi et al., 69(1) Cancer Treat. Res. 55-9 (1985); Fox et al., Medicinal Chemistry Advances, p. 27 (Pergamon Press, NY, 1981); and Fox et al., xe2x80x9cHerpes Viruses and Virus Chemotherapy,xe2x80x9d Pharmacological and Clinical Approaches, p. 53, (Excerpta Medica, Amsterdam, 1985). For example, 2xe2x80x2-fluoro-5-iodo-ara-cytosine (FIAC), 2xe2x80x2-fluoro-5-methyl-ara-uracil (FMAU), 2xe2x80x2-fluoro-5-methyl-ara uracil (FMAU) and 2xe2x80x2-fluoro-5-ethyl-ara uracil (FEAU) are active against DNA viruses, according to Lopez et al., 17(5) J. Antimicrob. Agents Chemother. 803-6 (1980); and Lin et al., 221 Science 519 (1983). Although certain 2xe2x80x2-fluoropurine derivatives are cytotoxic, others have been shown to possess anti-HIV activity. See, e.g., Chu et al., 37 Chem. Pharm. Bull. 336 (1989); and Marquez et al., 33 J. Med. Chem. 978 (1990). This is due to the fact that fluorine strategically positioned at sites of synthetic drugs and agrochemical products can significantly modify and/or enhance their biological activities. Fluorine mimics hydrogen with respect to steric requirements and contributes to an alteration of the electronic properties of the molecule. Increased lipophilicity and oxidative and thermal stabilities have been observed in such fluorine-containing compounds.
The conversion of the Cxe2x80x94O bond to the Cxe2x80x94F bond, which is referred to herein as deoxofluorination, represents a viable method to produce selectively fluorinated organic compounds. Deoxofluorination represents one technique which has been widely used for the selective introduction of fluorine into organic compounds. See, e.g., Boswell et al., 21 Org. React. 1 (1974). A list of the deoxofluorination methods generally used to fluorinate organic compounds to date includes: nucleophilic substitution via the fluoride anion; phenylsulfur trifluoride; fluoroalkylamines; sulfur tetrafluoride; SeF4; WF6; difluorophosphoranes and the dialkylaminosulfur trifluorides (DAST). The most common reagent of this class is diethylaminosulfur trifluoride, Et-DAST or simply DAST.
The DAST compounds have proven to be useful reagents for effecting deoxofluorinations. These reagents are conventionally prepared by reaction of N-silyl derivatives of secondary amines with SF4. In contrast to SF4, DAST compounds are liquids which can be used at atmospheric pressure and at near ambient to relatively low temperature (room temperature or below) for most applications. Deoxofluorination of alcohols and ketones is particularly facile and reactions can be carried out in a variety of organic solvents (e.g., CHCl3, CFCl3, glyme, diglyme, CH2Cl2, hydrocarbons, etc.). Most fluorinations of alcohols are done at a temperature within the range of xe2x88x9278xc2x0 C. to room temperature. Various functional groups are tolerated, including CN, CONR2, COOR (where R is an alkyl group), and successful fluorinations have been accomplished with primary, secondary and tertiary (1xc2x0, 2xc2x0, 3xc2x0) allylic and benzylic alcohols. The carbonyl to gem-difluoride transformation is usually carried out at room temperature or higher. Numerous structurally diverse aldehydes and ketones have been successfully fluorinated with DAST. These include acyclic, cyclic, and aromatic compounds. Elimination does occur to a certain extent when aldehydes and ketones are fluorinated and olefinic byproducts are also observed in these instances.
However, while the DAST compounds have shown versatility in effecting deoxofluorinations, there are several well-recognized limitations associated with their use. The compounds can decompose violently and while adequate for laboratory synthesis, they are not practical for large scale industrial use. In some instances, undesirable byproducts are formed during the fluorination process. Olefin elimination byproducts have been observed in the fluorination of some alcohols. Often, acid-catalyzed decomposition products are obtained. Moreover, the two-step synthesis employed with DAST compounds renders these relatively costly compositions only suitable for small scale syntheses.
The inventor and his colleagues have previously disclosed that other aminosulfur trifluorides, such as bis(2-methoxyethyl)aminosulfur trifluoride, are much safer to use than DAST and related aminosulfur trifluorides. See Lal et al., 64(19) J. Org. Chem. 7048 (1999); Lal et al., J. Chem. Soc. Chem. Commun. p. 215 (1999); U.S. Pat. No. 6,080,886 and U.S. patent application Ser. No. 08/939,635 filed Sep. 29, 1997. Compared to DAST compounds, bis(2-methoxyethyl)aminosulfur trifluorides provide more thermally stable fluorine-bearing compounds which have effective fluorinating capability with far less potential of violent decomposition and attendant high gaseous byproduct evolvement, with simpler and more efficient fluorinations. Furthermore, bis(2-methoxyethyl)aminosulfur trifluorides can efficiently effect the transformation of hydroxy and carbonyl functionalities to the corresponding fluoride and gem-difluoride respectively.
It has been observed that the direct replacement of a leaving group at the 2xe2x80x2-position of a pyrimidine nucleoside by the fluoride ion is complicated by neighboring-group participation of the carbonyl group of the base, resulting in the formation of the anhydronucleoside. See Fox, 18 J. Pure Appl. Chem. 223 (1969). In the synthesis of 2xe2x80x2-fluoropurines, attempts to replace a C2 protecting group (e.g., triflate) with fluoride resulted in base cleavage and formation of olefinic byproducts. See Pankiewicz et al., 64 J. Fl. Chem. 15 (1993). It has also been observed that the direct deoxofluorination of the 2xe2x80x2-hydroxyl of some purine derivatives by diethylaminosulfur trifluoride (DAST) afford only low yields of products even when a large excess of the fluorinating agent is used. See Pankiewicz et al., 57 J. Org. Chem. 553 (1992).
The synthesis of 2xe2x80x2-fluoro-substituted nucleosides is currently carried out by condensation of the appropriate 2-fluoro sugar derivative with the nucleoside base. See Pankiewicz et al., 15 J. Fl. Chem. 64 (1993). However, the fluoro sugar is not easily accessible since its preparation often involves lengthy multi-step and low yielding procedures. See Reichmann et al., 42 J. Cardohydr. Res. 233 (1975). The nucleophilic displacement of a leaving group by fluoride at C-2 of furanosides is often accompanied by elimination reactions resulting in olefinic byproducts. See Tann et al., 50 J. Org. Chem. 3644 (1985). Tann et al. reported on a three-step synthesis of 2-deoxy-2-fluoro-1,3,5-tri-O-benzoyl-xcex1-D-arabinofuranose via a 2-O-imidazolylsulfonate leaving group using KHF2 as the source of fluoride. Tann et al. found that the direct replacement of the C2-hydroxyl of this sugar by F with diethylaminosulfur trifluoride (DAST) failed.
Despite the findings in Tann et al., it has been shown that DAST has been used successfully for the deoxofluorination of hydroxy groups of six-membered ring sugars and the C3 hydroxyl of five-membered ring sugars (i.e., furanoses). See Welch et al., Fluorine in Bioorganic Chemistry, p. 131 (John Wiley and Sons, 1991). Additionally, the procedure of Tann et al. was improved upon by Chou et al. (37 Tett. Lett. 1 (1996)) where triethylamine poly(hydrogen fluoride) was used as the source of fluoride.
Accordingly, there remains a need in the art for a process effective to deoxofluorinate the C2-hydroxyl group of furanoses.
All references cited herein are incorporated herein by reference in their entireties.
The invention provides a process for deoxofluorinating a C2-hydroxyl group of a furanose. The process comprises mixing the furanose and a deoxofluorinating agent in a solvent to form a reaction mixture, and heating the reaction mixture to greater than about 50xc2x0 C.
Also provided are products produced by the process of the invention.
Not applicable.
A preferred process of the invention comprises deoxyfluorinating a hydroxylated ring carbon of a sugar with a fluorinating agent in the presence of a solvent. A preferred embodiment of the invention is shown in Equation I: 
where each of R, Rxe2x80x2 and Rxe2x80x3 is independently a protecting group or a group that does not react with the deoxofluorinating agent in the inventive process (unless it is desired to deoxofluorinate more than one carbon per molecule). Preferred protecting groups include esters, ethers, sulfonates, acetals and orthoesters. Particularly preferred protecting groups include benzoyl, trityl and triflate.
In embodiments, it is preferred to further modify the product of deoxofluorination to replace the protecting groups with hydrogen and/or to convert the sugar into a 2xe2x80x2-deoxy-2xe2x80x2-fluoro-arabinoside, wherein R of Equation I is a pyrimidine (e.g., cytosine, uracil or thymine) or a purine (e.g., adenine or guanine). Methods for coupling the sugar with a nucleoside base are known in the art. Thus, the invention provides an improved process for providing 2xe2x80x2-fluoropurines and 2xe2x80x2-fluoropyrimidines. The most preferred embodiments of the inventive process provide 2-fluoro-arabinose compounds and derivatives, including those previously shown to exhibit potent anti-tumor and anti-viral activity.
The preferred reactant to be deoxofluorinated is a five-membered ring sugar (i.e., a furanose) bearing a hydroxyl group solely at C2, wherein any additional hydroxyl groups have been replaced with a protecting group. Ribofuranoses are preferred reactants, but the invention is not limited thereto. For example, furanoses wherein C3 is unsubstituted (i.e., is bonded to two hydrogens) are also suitable reactants. The choice of reactant is largely influenced by the desired product. Ribofuranose reactants are most preferred as they provide 2-fluoro-arabinose products, such as 2-fluoro-1,3,5-tribenzoyl-xcex1-D-arabinofuranose, 3-deoxy-2-fluoro-1-methoxy-5-trityl-xcex1-D-arabinofuranose, and 2-fluoro-1,3,5-tribenzoyl-xcex1-L-arabinofuranose, which are preferred products of the invention.
After having the hydroxyl groups other than the C2 hydroxyl group protected (or selecting a sugar inherently containing groups other than the C2 hydroxyl group which are not reactive with the deoxofluorinating agent), the sugar to be deoxofluorinated is reacted with a deoxofluorinating agent in a solvent. Deoxofluorinating agents suitable for use in the invention include, e.g., diethylaminosulfur trifluoride (DAST), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor(trademark) reagent available from Air Products and Chemicals, Inc., Allentown, Pa.), perfluorobutanesulfonyl fluoride, 2-chloro-1,2,3-trifluoroethyldiethylamine (Yarovenko-Raksha reagent), and hexafluoroisopropyl diethylamine (Ishikawa reagent) and other aminosulfur trifluorides. Preferably, the deoxofluorinating agent is bis(2-methoxyethyl)aminosulfur trifluoride.
The deoxofluorination reaction of the present invention is conducted in the presence of a solvent. Preferably, the solvent does not react with the fluorinating agent. More preferably, the solvent is selected from the group consisting of hydrocarbons, halocarbons, ethers, amides, esters and mixtures thereof. Most preferably, the solvent is toluene. The solvent is preferably non-polar.
Preferably, the deoxofluorination is conducted at temperatures ranging from room temperature to less than the boiling point of the solvent. It is particularly preferred to combine the reactants in the solvent at room temperature and allow the reaction to progress at room temperature (i.e., without active heating) for a period of time before raising the temperature above 50xc2x0 C.. The mixing time without active heating is about 30 to 90 minutes, preferably about 1 hour. After this initial reaction period, the reaction mixture is preferably heated to greater than about 50xc2x0 C., more preferably about 90xc2x0 C., and mixed for an additional 90 minutes or more, preferably about 2 hours.
Thus, in particularly preferred embodiments, the reactants are combined in the solvent at room temperature, mixed without heating for about 1 hour, and heated to about 90xc2x0 C. with continued mixing for an additional 2 hours or so.
The reaction product is preferably isolated from the reaction mixture by quenching the reaction with an aqueous base, extracting the product in an organic solvent and distilling the solvent. The aqueous base is preferably NaHCO3. The solvent used for extraction is preferably the same solvent used as a medium for the reaction.
The product can be further purified by conventional techniques, such as chromatography or recrystallization.
Unlike conventional methods, the instant invention provides 2-fluoro-arabinose compounds in a yield ranging from about 83% to about 98% of theoretical.